Hung Truong Ngoc, Hung Nguyen Phi, Nghi Do Huu, Ha Nguyen Xuan, Loc Vu Thanh, Hai Pham The, Trang Luu Hanh, Cuong Nguyen Manh, Luu Van Chinh
Institute of Natural Products Chemistry, Vietnam Academy of Science and Technology, 18 Hoang Quoc Viet Str., Cau Giay, Hanoi, 100000, Vietnam.
Institute of Chemistry, Vietnam Academy of Science and Technology, 18 Hoang Quoc Viet Str., Cau Giay, Hanoi, 100000, Vietnam.
Chem Biodivers. 2025 Mar;22(3):e202401571. doi: 10.1002/cbdv.202401571. Epub 2024 Nov 20.
O-alkylation of the hydroxy compounds, including acetaminophen, starting compounds for the synthesis of the drug, and natural compounds with the bromides of dihydroartemisinin (DHA) and zerumbone, produced twenty novel ether conjugates 15a-j and 16a-j, respectively. Their structures were elucidated by 1D-, 2D-NMR, and HRMS data. Their in vitro cytotoxic activity was screened using three cancer cell lines: HepG2, HeLa, and PC-12. The results showed that eight out of ten conjugates in series 15a-j containing DHA skeleton exhibited activity against the tested cell lines, with IC values ranging from 4.26-47.37 μM. Notably, all conjugates in series 16a-j containing zerumbone scaffolds inhibited the growth of HepG2, HeLa, and PC12 with IC in the range of 4.46-35.07 μM. Using network pharmacology and molecular docking to target anti-liver cancer in the above 20 synthetic compounds, 271 intersection targets were discovered, including 5 targets with high degree values (EGFR, ESR1, AKT1, MDM2, and NFKB1). Artemisinin derivative 15i gave the highest binding energy for targets AKT1, EGFR, and NFKB1, while zerumbone-murrayafoline A ether 16g in the remaining series also gave the highest energy for proteins EGFR, AKT1, and NFKB1.
羟基化合物（包括对乙酰氨基酚、该药物合成的起始化合物以及天然化合物）与二氢青蒿素（DHA）和莪术酮的溴化物进行O-烷基化反应，分别生成了20种新型醚类共轭物15a-j和16a-j。通过一维、二维核磁共振以及高分辨质谱数据对它们的结构进行了阐明。使用三种癌细胞系（HepG2、HeLa和PC-12）对它们的体外细胞毒性活性进行了筛选。结果表明，含有DHA骨架的系列15a-j中的十种共轭物中有八种对测试细胞系表现出活性，IC值范围为4.26 - 47.37 μM。值得注意的是，含有莪术酮支架的系列16a-j中的所有共轭物均抑制HepG2、HeLa和PC12的生长，IC值范围为4.46 - 35.07 μM。利用网络药理学和分子对接方法对上述20种合成化合物中的抗肝癌靶点进行研究，发现了271个交集靶点，其中包括5个高值靶点（表皮生长因子受体、雌激素受体1、蛋白激酶B1、小鼠双微体2和核因子κB1）。青蒿素衍生物15i对靶点蛋白激酶B1、表皮生长因子受体和核因子κB1的结合能最高，而其余系列中的莪术酮-默里桉叶素A醚16g对蛋白表皮生长因子受体、蛋白激酶B1和核因子κB1也具有最高能量。
